Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Soluble alpha-klotho proteins, protein fragments, and uses thereof

a technology of soluble alpha-klotho proteins and protein fragments, which is applied in the field of modified soluble klotho proteins and isolated fragments of soluble klotho proteins, can solve the problems of inability to achieve parenteral regimens for chronic disorders, adverse effects of phosphate homeostasis on essentially every major tissue/organ, and insufficient replacement therapy alone. , to achieve the effect of suppressing egr1 transcription, promoting

Pending Publication Date: 2021-02-25
NEW YORK UNIV
View PDF0 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a modified soluble α-Klotho protein that has reduced binding affinity for fibroblast growth factor receptors (FGFRs) and a method of treating diseases or disorders mediated by interaction of FGF23 with an FGFR / α-Klotho complex. The modified soluble α-Klotho protein can be administered to patients in need thereof, such as those with renal phosphate wasting disorder, autosomal dominant hypophosphatemic rickets, tumor-induced osteomalacia, fibrous dysplasia, or chronic kidney disease. The invention also provides isolated fragments of wildtype soluble α-Klotho protein and pharmaceutical compositions containing the modified soluble α-Klotho protein or isolated fragment. The atomic structure of a 1:1:1:1 ternary complex consisting of the extracellular domain of α-Klotho, the ligand-binding domain of FGFR1c, and FGF23 is also described.

Problems solved by technology

Because of phosphate's pleiotropic activity, imbalances in phosphate homeostasis adversely affect essentially every major tissue / organ.
In addition, parenteral regimens are not practical for chronic disorders.
Most importantly, replacement therapy alone is never adequate when there is significant renal phosphate wasting.
It frequently causes the patients malnutrition and secondary osteoporosis.
This problem cannot be treated by a simple exogenous supplementation of phosphate.
Similar renal phosphate leakage with unknown pathology is often observed in pediatric medicine, with outcomes such as malnutrition or growth retardation.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Soluble alpha-klotho proteins, protein fragments, and uses thereof
  • Soluble alpha-klotho proteins, protein fragments, and uses thereof
  • Soluble alpha-klotho proteins, protein fragments, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 2

l Basis for αKlotho Co-Receptor Function

[0178]The crystal structure of a human 1:1:1 FGF23-FGFR1cecto-αKlothoect® ternary complex at 3.0 Å resolution was solved (Table 5). In this complex, αKlothoecto serves as a massive scaffold, tethering both FGFR1c and FGF23 to itself. In doing so, αKlothoecto enforces FGF23-FGFR1c proximity and thus augments FGF23-FGFR1c binding affinity (FIG. 1). The overall geometry of the ternary complex is compatible with its formation on the cell surface (FIG. 7A).

[0179]The binary FGF23-FGFR1cecto complex adopts a canonical FGF-FGFR complex topology in which FGF23 is bound between the receptor's D2 and D3 domains, engaging both these domains and a short interdomain linker (FIG. 8A). However, compared to paracrine FGFs, FGF23 makes fewer / weaker contacts with the D3 domain and D2-D3 linker, explaining the inherently low affinity of FGF23 for FGFR1c (FIGS. 8B-8C). Notably, analysis of the binding interface between FGF23 and FGFR1c D3 in the crystal structure ...

example 3

nterface Between αKlotho and FGFR1c

[0182]The interface between αKlotho RBA and FGFR1c D3 (FIG. 3A) buries over 2,200 Å2 of solvent-exposed surface area, which is consistent with the high affinity of αKlotho binding to FGFR1c (KD=72 nM)10. At the distal tip of the RBA, residues 547Tyr-Leu-Trp549 and 556Ile-Leu-Arg558 form a short β-strand pair (RBA-β1:RBA-β2) as their hydrophobic side chains are immersed in a wide hydrophobic groove between the four-stranded βC′-βC-βF-βG sheet and the βC-βC′ loop of FGFR1c D3 (FIG. 3B, upper panel). The RBA-β1:RBA-β2 strand pair forms an extended sheet with theβC′-βC-βF-βG sheet of D3 as the backbone atoms of RBA-β1 and D3 βC′ make three hydrogen bonds which further augment the interface (FIG. 3B, lower panel). Residues at the proximal end of the RBA engage a second smaller binding pocket at the bottom edge of D3 next to the hydrophobic groove (FIGS. 11A-11B). Both αKlotho binding pockets in the receptor D3 domain differ between “b” and “c” splice is...

example 4

nterface Between αKlotho and FGF23

[0184]Regions from both KL domains act together to recruit FGF23 (FIG. 1B), thus explaining why only an intact αKlotho ectodomain is capable of supporting FGF23 signaling (Kurosu et al., “Regulation of Fibroblast Growth Factor-23 Signaling by Klotho,”J. Biol. Chem. 281:6120-6123 (2006) and Wu et al., “C-Terminal Tail of FGF19 Determines its Specificity Toward Klotho Co-Receptors,”J. Biol. Chem. 283(48):33304-33309 (2008), each of which is hereby incorporated by reference in its entirety). The interactions between FGF23 and αKlotho result in the burial of a large amount of solvent-exposed surface area (2,732 Å2), of which nearly two-thirds (1961 Å2) are buried between the FGF23 C-terminal tail and αKlotho, with the remaining one-third buried between the FGF23 core and αKlotho (FIG. 3A). At the interface between αKlotho and FGF23 C-terminal tail, FGF23 residues 188Asp-Pro-Leu-Asn-Val-Leu193 adopt an unusual cage-like conformation (FIGS. 3A, 3C) which ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
emission energyaaaaaaaaaa
pHaaaaaaaaaa
pHaaaaaaaaaa
Login to View More

Abstract

Disclosed herein are modified soluble α-Klotho proteins and isolated fragments of wildtype soluble α-Klotho protein. Also disclosed are pharmaceutical compositions including the modified soluble α-Klotho proteins and / or isolated fragments of soluble α-Klotho protein and methods of their use in treating a subject.

Description

[0001]This application is a national stage application under 35 U.S.C. § 371 of PCT International Application No. PCT / US19 / 13282, filed Jan. 11, 2019, which claims the priority benefit of U.S. Provisional Application Ser. No. 62 / 616,945, filed Jan. 12, 2018, which is hereby incorporated by reference in its entirety.[0002]This invention was made with government support under grant number R01 DK091392 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates to modified soluble α-Klotho proteins and isolated fragments of soluble α-Klotho protein. The present invention also relates to compositions comprising such modified soluble α-Klotho proteins and / or isolated fragments of soluble α-Klotho protein, as well as methods of their use.BACKGROUND OF THE INVENTION[0004]Endocrine fibroblast growth factor 23 (FGF23) regulates phosphate and vitamin D homeostasis by reducing cell surface expression...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): C12N9/24A61K38/00
CPCC12N9/2402A61K38/00C12Y302/01031C07K14/71
Inventor MOHAMMADI, MOOSA
Owner NEW YORK UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com